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Medchemcomm. 2018 Oct 23;9(12):2055-2067. doi: 10.1039/c8md00448j. eCollection 2018 Dec 1.

Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1H)-one-3-carboxamide scaffold.

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School of Pharmacy , University of Otago , 18 Frederick Street , Dunedin 9054 , New Zealand . Email: ; Tel: +64 3 479 4518.
Department of Pharmacology and Clinical Pharmacology, and Centre for Brain Research , School of Medical Sciences , University of Auckland , Auckland , New Zealand.


Cannabinoid type 2 (CB2) receptor has been implicated in several diseases and conditions, however no CB2 receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB2 receptor tools, to enable an increased understanding of CB2 receptor expression and signalling and thereby accelerate drug discovery. Fluorescent ligands have been successfully developed for other receptors, however none with adequate subtype selectivity or imaging properties have been reported for CB2 receptor. A series of 1,8-naphthyridin-2-(1H)-one-3-carboxamides with linkers and fluorophores appended in the N1 and C3-positions were developed. Molecular modelling indicated the C3 cis-cyclohexanol-linked compounds directed the linker out of the CB2 receptor between transmembrane helices 1 and 7. Herein we report fluorescent ligand 32 (hCB2 pK i = 6.33 ± 0.02) as one of the highest affinity, selective CB2 receptor fluorescent ligands reported. Despite 32 displaying poor specific labelling of CB2 receptor, the naphthyridine scaffold with this linker remains highly promising for future development of CB2 receptor tools.

[Available on 2019-10-23]

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